Gault, L. M., R. A. Lenz, C. W. Ritchie, A. Meier, A. A. Othman, Q. Tang, S. Berry, Y. Pritchett, and W. Z. Robieson, "ABT-126 monotherapy in mild-to-moderate Alzheimer's dementia: randomized double-blind, placebo and active controlled adaptive trial and open-label extension.", Alzheimer's research & therapy, vol. 8, issue 1, pp. 44, 2016 Oct 18. AbstractWebsite

BACKGROUND: Results from a phase 2a study indicated that treatment with the novel α7 nicotinic acetylcholine receptor agonist ABT-126 25 mg once daily (QD) was associated with a trend for improvement in cognition in subjects with mild-to-moderate Alzheimer's dementia (AD). A phase 2b program was designed to evaluate a broader dose range of ABT-126 as monotherapy in subjects with mild-to-moderate AD. The program consisted of a double-blind, placebo and active controlled study of ABT-126 (dose range 25-75 mg) and an open-label extension study (75 mg).

METHODS: The randomized double-blind study enrolled 438 subjects (Mini-Mental Status Examination score of 10-24, inclusive) not currently taking acetylcholinesterase inhibitors or memantine. Subjects received 24 weeks of ABT-126 25 mg QD (n = 77), ABT-126 50 mg QD (n = 108), ABT-126 75 mg QD (n = 73), donepezil 10 mg QD (n = 76), or placebo (n = 104). The primary endpoint was the change from baseline to week 24 in the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) total score. Subjects completing the double-blind study could enroll in the 28-week open-label extension study. Adverse events (AEs) and other safety parameters were monitored in both studies.

RESULTS: A total of 367 patients (83.8 %) completed the double-blind study and 349 (79.7 %) entered the open-label study. Compared with placebo, donepezil significantly improved ADAS-Cog 11-item total scores from baseline to week 24 (-2.29 ± 0.95; one-sided P = 0.008). No ABT-126 dose demonstrated a statistically significant improvement vs placebo at week 24 in the ADAS-Cog total score: ABT-126 25 mg, -0.47 ± 0.94 (P = 0.309); ABT-126 50 mg, -0.87 ± 0.85 (P = 0.153); and ABT-126 75 mg, -1.08 ± 0.94 (P = 0.127). Rates of serious AEs and discontinuations due to AEs were similar across treatment groups. The most frequently reported AEs in both studies were constipation, fall, and headache. No clinically meaningful changes were observed in other parameters.

CONCLUSIONS: In the double-blind trial, donepezil significantly improved ADAS-Cog scores but no statistically significant improvement was seen with any ABT-126 dose. ABT-126 had an acceptable safety profile in subjects with mild-to-moderate AD in both studies.

TRIAL REGISTRATION: NCT01527916 , Registered 3 February 2012 (randomized trial). NCT01676935 . Registered 29 August 2012 (open-label extension study).

Genovese, M. C., J. S. Smolen, M. E. Weinblatt, G. R. Burmester, S. Meerwein, H. S. Camp, L. Wang, A. A. Othman, N. Khan, A. L. Pangan, et al., "Efficacy and Safety of ABT-494, a Selective JAK-1 Inhibitor, in a Phase IIb Study in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate.", Arthritis & rheumatology (Hoboken, N.J.), vol. 68, issue 12, pp. 2857-2866, 2016 Dec. AbstractWebsite

OBJECTIVE: To evaluate the efficacy and safety of ABT-494, a selective JAK-1 inhibitor, in patients with moderate-to-severe rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX).

METHODS: Three hundred RA patients receiving stable doses of MTX were randomly assigned equally to receive immediate-release ABT-494 at 3, 6, 12, or 18 mg twice daily, 24 mg once daily, or placebo for 12 weeks. The primary efficacy end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 12, as determined using the last observation carried forward method.

RESULTS: At week 12, the proportion of ACR20 responses was higher with ABT-494 (62%, 68%, 80%, 64%, and 76% for the 3, 6, 12, 18, and 24 mg doses, respectively) than with placebo (46%) (using nonresponder imputation) (P < 0.05 for the 6, 12, and 24 mg doses). There was a significant dose-response relationship among all ABT-494 doses (P < 0.001). The proportions of patients achieving ACR50 and ACR70 responses were significantly higher for all ABT-494 doses (except the 12 mg dose for the ACR70 response) than for placebo, as were changes in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP). Rapid improvement was demonstrated by significant differences in ACR20 response rates and changes in the DAS28-CRP for all doses compared with placebo at week 2 (the first postbaseline visit). The incidence of adverse events was similar across groups; most were mild, and infections were the most frequent. One serious infection (community-acquired pneumonia) occurred with ABT-494 at 12 mg. There were dose-dependent increases in high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, but the LDL cholesterol:HDL cholesterol ratios were unchanged through week 12. Mean hemoglobin levels remained stable at lower doses, but decreases were observed at higher doses.

CONCLUSION: This study evaluated a broad range of doses of ABT-494 in RA patients with an inadequate response to MTX. ABT-494 demonstrated efficacy, with a safety and tolerability profile similar to that of other JAK inhibitors.

Kremer, J. M., P. Emery, H. S. Camp, A. Friedman, L. Wang, A. A. Othman, N. Khan, A. L. Pangan, S. Jungerwirth, and E. C. Keystone, "A Phase IIb Study of ABT-494, a Selective JAK-1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti-Tumor Necrosis Factor Therapy.", Arthritis & rheumatology (Hoboken, N.J.), vol. 68, issue 12, pp. 2867-2877, 2016 Dec. AbstractWebsite

OBJECTIVE: To compare the efficacy and safety of ABT-494, a novel selective JAK-1 inhibitor, with placebo in patients with moderate-to-severe rheumatoid arthritis (RA) and an inadequate response or intolerance to at least 1 anti-tumor necrosis factor (anti-TNF) agent.

METHODS: In this 12-week, double-blind, placebo-controlled, dose-ranging study, 276 RA patients receiving a stable dose of methotrexate (MTX) who had previously received treatment with at least 1 anti-TNF agent were randomized equally to receive immediate-release ABT-494 at 3, 6, 12, or 18 mg twice daily or matching placebo twice daily. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 12.

RESULTS: At week 12, significantly more patients receiving ABT-494 (53-71%) than those receiving placebo (34%) achieved an ACR20 response (by nonresponder imputation analysis) (P < 0.05), with a dose-response relationship among all ABT-494 doses (P < 0.001). ACR50 and ACR70 response rates were significantly higher in those receiving ABT-494 (36-42% and 22-26%, respectively) than in those receiving placebo (16% and 4%, respectively). Changes from baseline in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) were significantly greater for all doses of ABT-494 than for placebo (P ≤ 0.01). Onset of action of ABT-494 was rapid, with significant differences from placebo at week 2 both in ACR20 response rate (for 12 and 18 mg) and in change in the DAS28-CRP (P < 0.001 for 6-18 mg). The most frequent adverse events (AEs) were headache, nausea, upper respiratory tract infection, and urinary tract infection. Infection rates were higher at higher doses of ABT-494, but no infections were serious. No deaths were reported among those receiving ABT-494.

CONCLUSION: In patients with an inadequate response or intolerance to anti-TNF agents, ABT-494 added to MTX showed rapid, dose-dependent improvements in RA signs and symptoms, with safety and tolerability similar to those of other drugs of this class. No new AEs were identified.

Diao, L., Y. Hang, A. A. Othman, D. Mehta, L. Amaravadi, I. Nestorov, and J. Q. Tran, "Population PK-PD analyses of CD25 occupancy, CD56(bright) NK cell expansion, and regulatory T cell reduction by daclizumab HYP in subjects with multiple sclerosis.", British journal of clinical pharmacology, vol. 82, issue 5, pp. 1333-1342, 2016 Nov. AbstractWebsite

AIM: Daclizumab high yield process (HYP) is a humanized IgG1 monoclonal antibody that binds to the α-subunit of the interleukin-2 receptor and is being developed for treatment of multiple sclerosis (MS). This manuscript characterized the pharmacokinetic-pharmacodynamic (PK-PD) relationships of daclizumab HYP in subjects with MS.

METHODS: Approximately 1400 subjects and 7000 PD measurements for each of three biomarkers [CD25 occupancy, CD56(bright) natural killer (NK) cell count, regulatory T cell (Treg) count] from four clinical trials were analyzed using non-linear mixed effects modelling. Evaluated regimens included 150 or 300 mg subcutaneous (s.c.) every 4 weeks.

RESULTS: CD25 occupancy was characterized using a sigmoidal maximum response (Emax ) model. Upon daclizumab HYP treatment, CD25 saturation was rapid with complete saturation occurring after approximately 7 h and maintained when daclizumab HYP serum concentration was ≥5 mg l(-1) . After the last 150 mg s.c. dose, unoccupied CD25 returned to baseline levels in approximately 24 weeks, with daclizumab HYP serum concentration approximately ≤1 mgl(-1) 1L. CD56(bright) NK cell expansion was characterized using an indirect response model. Following daclizumab HYP 150 mg s.c. every 4 weeks, expansion plateaus approximately at week 36, at which the average maximum expansion ratio is 5.2. After the last dose, CD56(bright) NK cells gradually declined to baseline levels within 24 weeks. Treg reduction was characterized by a sigmoidal Emax model. Average maximum reduction of 60% occurred approximately 4 days post 150 mg s.c. dose. After the last dose, Tregs were projected to return to baseline levels in approximately 20 weeks.

CONCLUSIONS: Robust PK-PD models of CD25 occupancy, CD56(bright) NK cell expansion and Treg reduction by daclizumab HYP were developed to characterize its key pharmacodynamic effects in the target patient population.

Haig, G., D. Wang, A. A. Othman, and J. Zhao, "The α7 Nicotinic Agonist ABT-126 in the Treatment of Cognitive Impairment Associated with Schizophrenia in Nonsmokers: Results from a Randomized Controlled Phase 2b Study.", Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, vol. 41, issue 12, pp. 2893-2902, 2016 Nov. AbstractWebsite

A double-blind, placebo-controlled, parallel-group, 24-week, multicenter trial was conducted to evaluate the efficacy and safety of 3 doses of ABT-126, an α7 nicotinic receptor agonist, for the treatment of cognitive impairment in nonsmoking subjects with schizophrenia. Clinically stable subjects were randomized in 2 stages: placebo, ABT-126 25 mg, 50 mg or 75 mg once daily (stage 1) and placebo or ABT-126 50 mg (stage 2). The primary analysis was the change from baseline to week 12 on the MATRICS Consensus Cognitive Battery (MCCB) neurocognitive composite score for ABT-126 50 mg vs placebo using a mixed-model for repeated-measures. A key secondary measure was the University of California Performance-based Assessment-Extended Range (UPSA-2ER). A total of 432 subjects were randomized and 80% (344/431) completed the study. No statistically significant differences were observed in either the change from baseline for the MCCB neurocognitive composite score (+2.66 [±0.54] for ABT-126 50 mg vs +2.46 [±0.56] for placebo at week 12; P>0.05) or the UPSA-2ER. A trend for improvement was seen at week 24 on the 16-item Negative Symptom Assessment Scale total score for ABT-126 50 mg (change from baseline -4.27±[0.58] vs -3.00±[0.60] for placebo; P=0.059). Other secondary analyses were generally consistent with the primary end point results. Adverse event rates were similar for ABT-126 and placebo. ABT-126 did not demonstrate a consistent effect on cognition in nonsmoking subjects with schizophrenia; however, a trend toward an effect was observed on negative symptoms. registration: NCT01655680.

Mohamed, M. - E. F., H. S. Camp, P. Jiang, R. J. Padley, A. Asatryan, and A. A. Othman, "Pharmacokinetics, Safety and Tolerability of ABT-494, a Novel Selective JAK 1 Inhibitor, in Healthy Volunteers and Subjects with Rheumatoid Arthritis.", Clinical pharmacokinetics, vol. 55, issue 12, pp. 1547-1558, 2016 Dec. AbstractWebsite

BACKGROUND: ABT-494 is a potent and selective Janus kinase (JAK) 1 inhibitor being developed for the treatment of several autoimmune disorders, with potential for an improved safety profile compared with non-selective JAK inhibitors. This work characterized the pharmacokinetics, safety, and tolerability of ABT-494 following single and multiple dosing of the immediate-release formulation.

METHODS: ABT-494 single (1-48 mg or placebo; n = 56) and multiple (3-24 mg or placebo twice daily for 14 days; n = 44) doses in healthy subjects, as well as multiple doses (3-24 mg or placebo twice daily for 27 days; n = 14) in subjects with rheumatoid arthritis (RA) on a background of methotrexate were evaluated. Pharmacokinetic samples were collected and safety and tolerability were assessed.

RESULTS: ABT-494 followed bi-exponential disposition, with a terminal elimination half-life of 6-16 h and a functional half-life, calculated from maximum observed plasma concentration (C max) to trough plasma concentration (C trough) ratio at steady state, of 3-4 h. ABT-494 exposure was approximately dose proportional over the 3-36 mg dose range, with no significant accumulation with repeated dosing. In subjects with RA, no pharmacokinetic interaction between ABT-494 and methotrexate was observed. The fraction of ABT-494 dose eliminated in urine as unchanged ABT-494 was 14-25 %. All treatment-emergent adverse events (TEAEs) were mild or moderate in severity, with headache being the most frequently observed TEAE (15.6 % for ABT-494 vs. 16.7 % for placebo) after multiple twice-daily administration to healthy subjects. No clinically significant changes in laboratory parameters, vital signs, or electrocardiogram findings in healthy or RA subjects were observed.

CONCLUSIONS: The favorable pharmacokinetics, safety, and tolerability results from these studies supported further evaluations of ABT-494 in phase IIb dose-ranging trials in RA and Crohn's disease.

TRIAL REGISTRATION: ( ) identifier: NCT01741493.

Tran, J. Q., A. A. Othman, P. Wolstencroft, and J. Elkins, "Therapeutic protein-drug interaction assessment for daclizumab high-yield process in patients with multiple sclerosis using a cocktail approach.", British journal of clinical pharmacology, vol. 82, issue 1, pp. 160-7, 2016 Jul. AbstractWebsite

AIMS: To characterize the potential effect of daclizumab high-yield process (DAC HYP), a monoclonal antibody that blocks the high-affinity interleukin-2 receptors for treatment of multiple sclerosis, on activity of cytochrome P450 (CYP) enzymes.

METHODS: Twenty patients with multiple sclerosis received an oral cocktail of probe substrates of CYP1A2 (caffeine 200 mg), CYP2C9 (warfarin 10 mg/vitamin K 10 mg), CYP2C19 (omeprazole 40 mg), CYP2D6 (dextromethorphan 30 mg) and CYP3A (midazolam 5 mg) on two sequential occasions: 7 days before and 7 days after subcutaneous administration of DAC HYP 150 mg every 4 weeks for three doses. Serial pharmacokinetic blood samples up to 96 h post dose and 12-h urine samples were collected on both occasions. Area under the curve (AUC) for caffeine, S-warfarin, omeprazole and midazolam, and urine dextromethorphan to dextrorphan ratio were calculated. Statistical analyses were conducted on log-transformed parameters using a linear mixed-effects model.

RESULTS: The 90% confidence intervals (CIs) for the geometric mean ratio (probe substrate with DAC HYP/probe substrate alone) for caffeine AUC from 0-12 h (0.93-1.15), S-warfarin AUC from 0 to infinity (AUC[0-inf]) (0.95-1.06), omeprazole AUC(0-inf) (0.88-1.13) and midazolam AUC(0-inf) (0.89-1.15) were within the no-effect boundary of 0.80-1.25. The geometric mean ratio for urine dextromethorphan to dextrorphan ratio was 1.01, with the 90% CI (0.76-1.34) extending slightly outside the no-effect boundary, likely due to high variability with urine collections and CYP2D6 activity.

CONCLUSIONS: DAC HYP treatment in patients with multiple sclerosis had no effect on CYP 1A2, 2C9, 2C19, 2D6 and 3A activity.

Florian, H., A. Meier, S. Gauthier, S. Lipschitz, Y. Lin, Q. Tang, A. A. Othman, W. Z. Robieson, and L. M. Gault, "Efficacy and Safety of ABT-126 in Subjects with Mild-to-Moderate Alzheimer's Disease on Stable Doses of Acetylcholinesterase Inhibitors: A Randomized, Double-Blind, Placebo-Controlled Study.", Journal of Alzheimer's disease : JAD, vol. 51, issue 4, pp. 1237-47, 2016. AbstractWebsite

BACKGROUND: ABT-126 is a potent, selective α7 nicotinic acetylcholine receptor agonist with putative procognitive effects as a monotherapy in treating Alzheimer's disease (AD).

OBJECTIVE: This randomized, double-blind, placebo-controlled multicenter study (NCT01549834) investigated the efficacy and safety of ABT-126 in subjects with mild-to-moderate AD who were taking stable doses of acetylcholinesterase inhibitors (AChEIs).

METHODS: Subjects received 25 mg ABT-126 (n = 143), 75 mg ABT-126 (n = 145), or placebo (n = 146) once daily for 24 weeks. Subjects who completed the 24-week double-blind study were eligible to enroll in a 28-week open-label extension study (NCT01690195) and received 75 mg ABT-126 daily. The primary efficacy endpoint was the change from baseline to week 24 in the 11-item total score of the Alzheimer's Disease Assessment Scale- Cognitive Subscale (ADAS-Cog).

RESULTS: Neither dose of ABT-126 demonstrated significant improvement compared with placebo in the primary efficacy endpoint. However, 25 mg ABT-126 demonstrated significant improvement compared with placebo in ADAS-Cog scores at week 4 (least squares mean difference, -1.21; standard error, 0.51; p <  0.010, one-sided); 75 mg ABT-126 did not demonstrate significant improvements in ADAS-Cog scores compared with placebo at any time point. A treatment effect was not observed for any secondary efficacy measures of cognition, function, or global improvement. ABT-126 was generally well tolerated; the most common adverse events were agitation, constipation, diarrhea, fall, and headache.

CONCLUSIONS: Overall, the efficacy profile of ABT-126 did not warrant further development as add-on therapy to AChEIs to treat mild-to-moderate AD.

Haig, G. M., E. E. Bain, W. Z. Robieson, J. D. Baker, and A. A. Othman, "A Randomized Trial to Assess the Efficacy and Safety of ABT-126, a Selective α7 Nicotinic Acetylcholine Receptor Agonist, in the Treatment of Cognitive Impairment in Schizophrenia.", The American journal of psychiatry, vol. 173, issue 8, pp. 827-35, 2016 Aug 01. AbstractWebsite

OBJECTIVE: The authors sought to evaluate the efficacy and safety of ABT-126, a selective α7 nicotinic receptor partial agonist, in stable patients with schizophrenia.

METHOD: A 12-week, double-blind, placebo-controlled, parallel-group phase 2 study was conducted in 22 centers in the United States. Clinically stable patients with schizophrenia were randomly assigned to receive once-daily dosing with 10 mg of ABT-126, 25 mg of ABT-126, or placebo. The primary efficacy measure was change from baseline to week 12 on the MATRICS Consensus Cognitive Battery (MCCB) composite score compared with placebo, tested by a one-sided t test. Secondary measures included MCCB domain scores and UCSD Performance-Based Skills Assessment total score, each tested by two-sided t tests.

RESULTS: A total of 207 subjects were randomized, of whom 165 (81%) completed the study. ABT-126 showed an improvement that fell short of significance on the MCCB composite score at week 12 (least squares mean difference from placebo, 1.3 and 1.5 for the 10 mg and 25 mg groups, respectively). A significant treatment-by-smoking status interaction was observed on the mean change from baseline to final MCCB composite score: nonsmokers (N=69) demonstrated a difference from placebo of 2.9 (SE=1.4) in the 10 mg group and 5.2 (SE=1.6) in the 25 mg group, whereas no differences were observed in smokers (N=113). Among the nonsmokers in the ABT-126 25 mg group (N=19), significant improvements compared with placebo occurred at final assessment for verbal learning (least squares mean difference=5.5, SE=1.9), working memory (least squares mean difference=5.4, SE=2.0), and attention/vigilance (least squares mean difference=8.7, SE=2.5). The most frequently reported adverse events for ABT-126 were dizziness, diarrhea, and fatigue (all <8% incidence).

CONCLUSIONS: ABT-126 demonstrated a procognitive effect in nonsmoking subjects, particularly in verbal learning, working memory, and attention.

Tran, J. Q., A. A. Othman, A. Mikulskis, P. Wolstencroft, and J. Elkins, "Pharmacokinetics of daclizumab high-yield process with repeated administration of the clinical subcutaneous regimen in patients with relapsing-remitting multiple sclerosis.", Clinical pharmacology : advances and applications, vol. 8, pp. 9-13, 2016. AbstractWebsite

BACKGROUND: Daclizumab high-yield process (DAC HYP), a humanized immunoglobulin G1 monoclonal antibody specific for the α subunit (CD25) of the high-affinity interleukin-2 receptor, has demonstrated efficacy for treatment of relapsing forms of multiple sclerosis in Phase II and III clinical trials.

OBJECTIVE: To characterize the pharmacokinetics (PK) of DAC HYP following repeated administration of the 150 mg subcutaneous (SC) dose every 4 weeks (q4wk), the proposed clinical regimen in patients with relapsing-remitting multiple sclerosis (RRMS).

METHODS: Twenty-six patients with RRMS received DAC HYP 150 mg SC q4wk for a total of six doses. Serial PK blood samples were collected over the first and last dosing intervals and trough PK samples were collected between these doses. Blood samples for immunogenicity assessment were collected throughout the study. Serum DAC HYP levels and anti-DAC HYP antibodies were characterized using validated immunoassays. PK parameters were estimated using noncompartmental analysis.

RESULTS: DAC HYP showed slow SC absorption with a median time to reach maximum observed concentration (Cmax) value of ~1 week. Steady state was reached by the fourth injection. At steady state, DAC HYP mean serum Cmax, minimum observed concentration (Cmin), and area under the concentration-time curve within a dosing interval (AUCtau) values were 29.1 µg/mL, 14.9 µg/mL, and 638 µg · day/mL, respectively, with intersubject variability of 35%-40%. The AUC accumulation ratio was ~2.5 at steady state. DAC HYP had a long elimination half-life of ~22 days and low apparent clearance (0.274 L/day). Nine patients tested positive for anti-DAC HYP antibodies, with no impact on DAC HYP clearance in this limited data set.

CONCLUSION: The PK of DAC HYP in patients with RRMS are consistent with those previously reported in healthy volunteers. The half-life of ~3 weeks and the low fluctuations in peak and trough concentrations of serum DAC HYP support the once-monthly SC dosing regimen.